Paul Doetsch

Evolutionary theory says mutations are blind and occur randomly. But in theÂ controversialÂ phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.

Scientists at Winship Cancer Institute, Emory University have observed that an apparent “back channel” for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.

“This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how mutations in cancer cells enable their growth or resistance to chemotherapy drugs,” says senior author Paul Doetsch, PhD.

Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is Genetics and Molecular Biology graduate student Jordan Morreall, PhD, who defended his thesis in April.

Retromutagenesis resolves the puzzle: if cells arenâ€™t growing because theyâ€™re under stress, which means their DNA isnâ€™t being copied, how do the new mutants appear?

First approved by the FDA in the 1970s, the chemotherapy drug cisplatin and its relative carboplatin remain mainstays of treatment for lung, head and neck, testicular and ovarian cancer. However, cisplatinâ€™s use is limited by its toxicity to the kidneys, ears and sensory nerves.

Paul Doetschâ€™s lab at Winship Cancer Institute has made some surprising discoveries about how cisplatin kills cells. By combining cisplatin with drugs that force cells to rely more on mitochondria, it may be possible to target it more specifically to cancer cells and/or reduce its toxicity.

Cisplatin emerged from a serendipitous discovery in the 1960s by a biophysicist examining the effects of electrical current on bacterial cell division. It wasnâ€™t the current that stopped the bacteria from dividing â€“ it was the platinum in the electrodes. According to Siddhartha Mukherjeeâ€™s book The Emperor of All Maladies, cisplatin became known as â€œcisflattenâ€ in the 1970s and 1980s because of its nausea-inducing side effects.

Cisplatin is an old-school chemotherapy drug, in the sense that itâ€™s a DNA-damaging agent with a simple structure. It doesnâ€™t target cancer cells in some special way, it just grabs DNA with its metallic arms and holds on, forming crosslinks between DNA strands.

But how cisplatin kills cells is more complicated. Along with the direct effects of DNA damage, cisplatin unleashes a storm of reactive oxygen species.

â€œWe wanted to know whether the reactive oxygen species induced by cisplatin had a driving role in cell death or was more of a byproduct,â€ says postdoc Rossella Marullo, who is the first author of a recent paper with Doestch in PLOS One.

One possible analogy: after the 1906 San Francisco earthquake, the fires were even more destructive than the initial shaking. When asked whether to think of the reactive oxygen species production triggered by cisplatin in the same way as the fires, Doetsch and Marullo say they wouldnâ€™t go that far.

Still, they have uncovered a critical role for mitochondria, cellsâ€™ mini-power plants, in cisplatin cell toxicity. The researchers found that mitochondria are the source of cisplatin-induced reactive oxygen species in lung cancer cells. Cancer cell lines that lack functional mitochondria* are less sensitive to cisplatin, and cisplatinâ€™s damage to the mitochondria may be even more important than the damage to DNA in the nucleus, the authors write. However, mitochondrial damage is not important for cisplatinâ€™s less potent [but less toxic] cousin carboplatin.

Cancer cells tend to have a warped metabolism that makes them turn off their mitochondria. This is part of the â€œWarburg effectâ€ (experts in this area: Winship’s Jing Chen and Malathy Shanmugam). Cancer cells have an increased uptake of sugar, but donâ€™t break it down completely, and use the byproducts as building materials.

What if we could force cancer cells to rely on their mitochondria again, and at the same time, by giving them cisplatin, make that painful for them? This would make cisplatin even more toxic to cancer cells in particular.

The drug DCA (dichloroacetate), which can stimulate cancer cells to use their mitochondria, can also increase the toxicity of cisplatin, at least in cancer cell lines in the laboratory, Marullo and her colleagues show.

Doetsch and radiation oncologist Jonathan Beitler are in the process of planning a clinical trial combining DCA with cisplatin for HPV (human papillomavirus)-positive head and neck cancer. The trial would test whether it might be possible to use a lower dose of cisplatin, reducing toxicity, by combining it with DCA.

â€œWeâ€™ve relied on cisplatinâ€™s efficacy for decades, without fully understanding the mechanism,â€ Beitler says. â€œWith this new knowledge, it may be possible to manipulate cisplatinâ€™s action so it is more effective and less toxic.â€

The applicability of cisplatin and mitochondrial tuning may depend both on cancer cell type and metabolic state, Doetsch adds.

*Cell lines that lack mitochondrial DNA can be obtained by “pickling” them in ethidium bromide, a DNA intercalation agent.

Cancer researcher Paul Doetsch is a prominent voice in a recent feature in Science magazine’s Careers section. The article gives scientists who are setting up their laboratories advice on how to manage their laboratories and lead by example.

Doetsch holds a distinguished chair of cancer research and is associate director for basic research at Winship Cancer Institute. His research on how cells handle DNA damage has provided insights into mechanisms of tumor formation and antibiotic resistance.Â His lab includes five graduate students, two senior postdocs and one technical specialist.

From the article:

Doetsch says that he tries to maintain a lab culture that provides technicians, students, postdocs, and research faculty a sense of â€œownershipâ€ of their projects and to give the message everyone is making a significant contribution to the research enterprise, regardless of their specific title or role. “I make it a point to walk around my lab several times a day to chat with my group and hold individual weekly research meetings with each member to get an update of their progress and provide them with direct, constructive feedback on their activities,” he says. “I always strongly encourage everyone to discuss their results and other issues affecting their project with their lab colleagues and to not hesitate to disagree with me when necessary.â€